Finished Product Inspection: Automation, Complex Therapeutics, and Quality Standards
With over 30 years of pharmaceutical experience, Brian Korson, Director of Finishing Operations at Grand River Aseptic Manufacturing (“GRAM”), has extensive knowledge of product inspection, quality assurance, packaging, and operations. Brian discusses the intricacies of drug product inspection, determining whether manual, semi-automated, or automated inspection is best for your drug product, and more.
Can you briefly describe the evolution of finished product inspections in the pharma and biopharma industry?
USP <1> first defined that injections were to be essentially free of visible particulate. That USP definition was very ambiguous, as there were no clear guidelines as to what an acceptable level of particulate matter was in injectables. In August of 2014, USP <790> was published and provided some clarity of “essentially free”. Following 100% visual inspection under controlled lighting and time conditions, an acceptable AQL sampling using 0.65% acceptance criteria was considered as meeting the definition of “essentially free” of particulate matter. Since USP <790> was published, further guidance in product acceptance has been published including USP <1790>, Visual Inspection of Parenterals, and PDA Technical Report 79, Particulate Matter Control in Difficult to Inspect Parenterals. As the industry has evolved, the expectation is that units are produced with controls to minimize particulate, perform 100% visual inspection removing defects including particulate, know the particulate your process can produce, and continually improve to eliminate them.
Can you provide an overview of the product assessment process for visual inspection of new finished product at GRAM? How do you ensure finished products meet quality standards?
When new products come into GRAM, the container closure, fill level, and product type are reviewed. If those attributes fall into GRAMs bracketing approach, meaning we have experience with it and have proved the ability to cull defects, no further evaluation is needed. If they fall outside our previous experience, GRAM will execute probability of detection studies. We develop inspection test kits that have good containers along with defect containers with cosmetic and particulate of various materials and sizes. A group of inspectors inspect these sets multiple times to get a detectability profile. For critical defects we must remove 100% of the defects, 80% for major and minor defects, and reject no more than 5% good vials. If the inspection method is unable to do that, we modify the method and repeat until those levels are achieved. If that cannot be achieved, the product is deemed difficult to inspect and we implement alternate verification methods outlined in the PDA technical report to assure the product is essentially free of particulate and defects.
What are the stages of finished product inspection? What are the criteria for manual, semi-automated, and fully automated inspection, and when is each inspection method appropriate?
The first stage of finished product inspection is determining whether your inspection process can detect defects in a pharmaceutical presentation. That is accomplished via the probability of detection studies explained above. Once that is achieved, your inspection method, manual, semi-automatic, or fully automated is determined. Sometimes semi-automated or automated inspection isn’t an option, and we remain with standard manual inspection. If the other options are available, typically we determine the method based on the lot size. For lot sizes under 5,000 we like to stay with manual inspection. For lot sizes between 5,000 and 15,000 we choose semi-automatic inspection. For lot sizes above 15,000, fully automated inspection is preferred.
What are the different types of inspection technologies GRAM uses? Have there been any recent technological advancements or updates in your inspection processes?
GRAM utilizes all three types of inspection: manual, semi-automated, and fully automated inspection. All our recipes for semi-automated and fully automated inspection are tied back to manual visual inspection detection data. Recipes on those systems are only able to be utilized if the recipe is proven to detect defects equal to or better than manual visual inspection. GRAM has unique inspection technologies in place. First, for our clients in a vial with a freeze-dried product we utilize a Lighthouse inspection machine to verify container closure integrity (CCI). This is a laser-based system that can verify CCI via pressure detection or oxygen presence, which supports recent Annex 1 guidelines. Second, our fully automated vial inspection equipment has a feature for CCI verification utilizing high-voltage leak detection (HVLD). This feature increases the ability to detect small container breaches. Finally, our newest automated inspection machines for vials and syringes can use artificial intelligence to refine the recipe for better defect detection and mitigate false rejects.
How is the pharma industry’s move towards more complex therapeutics impacting inspection processes?
Products, especially on the vaccine side, increasingly need to be fully filled, inspected, and packaged in short time frames to get them into their final refrigerated or frozen states. What used to last days must now be completed in hours. The only way to achieve this with large batch sizes is with fully automated inspection and packaging equipment performing at extremely high speeds. GRAM’s inspection and packaging equipment is validated up to 500 vials per minute, allowing us to meet these strict requirements.
Unique container closure systems such as syringes and cartridges also add to the difficulties in inspection. Each of these container closure systems provides challenges for manual and automated inspection. These systems have unique attributes that could contain defects that inspectors must learn and add to the recipes for automated equipment. Additional training and test kits must be maintained and used to qualify inspectors and automated equipment.
What are the benefits of automating the inspection process, either fully or partially?
Two main benefits of automating the inspection process are speed and repeatability. As timelines for processing get less and less, having the ability to complete inspection quickly is paramount. A manual inspection department would need enormous human and space capital to achieve the same throughput as automated inspection. In addition to speed, automated equipment allows for repeatability. The equipment does not tire in the way humans could during manual inspection.
There are some drawbacks to automated inspection. The inspection on automated equipment is only as good as the defective samples used to program the recipe. Manual inspectors can adapt and recognize new defects never seen before in a process. Automated equipment cannot necessarily do that. However, with the advent of AI technology, the hope is that this adaptive, learning nature of human inspectors can occur in automated inspection equipment.
How are regulatory bodies adapting to the automation of finished product inspection? Are there any new guidelines that companies should be aware of?
The FDA (Food and Drug Administration) published a guidance document in December 2021, Inspection of Injectable Products for Visible Particulate. This document speaks to inspection, with a generous part on the use of automated visual inspection equipment, and shows regulatory bodies are becoming increasingly more comfortable with its use. It is important to have strong manual inspection data on products, understanding the inherent and unique defects associated with those products. This allows for development of sound recipes for the automated equipment and gives regulatory bodies confidence in your automated equipment.
Are there current trends or challenges impacting finished product inspection or any future trends that you see having an impact on the industry?
Annex 1 will have a substantial impact on pharmaceutical inspection, especially with freeze dried products. Annex 1 has a directive that says, “Containers sealed under vacuum are to be tested for the maintenance of the vacuum after a previously defined, appropriate period of time and during shelf life.” We are using our Lighthouse machine for freeze dried products to meet this requirement.
